DESCRIPTION: (Applicant's Abstract) This is an application for competitive renewal of K-series career award support for years 21-25. The focus of the applicant's research career is on the human behavioral pharmacology of drug abuse. The applicant directs a large and multi faceted clinical research program that includes two major components: (1) residential human laboratory studies related to the clinical pharmacology of opioids, of cocaine, and of potential pharmacotherapies for opioid or cocaine dependence; and (2) outpatient controlled clinical trials of behavioral and pharmacological treatments for opioid or cocaine dependence. The research program is also the site of a postdoctoral research training program, which has a history of training productive new scientists as drug abuse researchers, and of which the applicant is director. The applicant proposes to continue as research program director, and as training program director, and to conduct during this renewal period an inter-related series of human laboratory studies and outpatient clinical trials directed toward the behavioral pharmacological understanding and treatment of opioid and cocaine abuse. The opioid clinical pharmacology studies will evaluate the effects of opioids with kappa-receptor agonist activity in comparison to mu-receptor agonists, and will assess and characterize the effects of an opioid antagonist combination product (buprenorphine plus naloxone) that is being developed as an opioid dependence pharmacotherapy. The cocaine clinical pharmacology studies will test potential anti-cocaine pharmacotherapies by assessing whether response to cocaine challenge is altered by pretreatment with various agents (chronic oral cocaine, the opioid kappa agonist enadoline, the serotonergic agent tryptophan). The opioid dependence clinical trials will compare the efficacy and patient acceptability of three opioid agonist substitution pharmacotherapies (methadone, LAAM, buprenorphine). The cocaine dependence clinical trials will evaluate the efficacy of the serotonergic agents tryptophan and fluoxetine in the context of an incentive-based behavior therapy program.